US4558050A - Treatment of metabolic disorders with dichloroacetate-thiamine preparations - Google Patents
Treatment of metabolic disorders with dichloroacetate-thiamine preparations Download PDFInfo
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- US4558050A US4558050A US06/584,994 US58499484A US4558050A US 4558050 A US4558050 A US 4558050A US 58499484 A US58499484 A US 58499484A US 4558050 A US4558050 A US 4558050A
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- salt
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- thiamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D415/00—Heterocyclic compounds containing the thiamine skeleton
Definitions
- the present invention relates to novel compounds and compositions, useful for the treatment of certain metabolic diseases.
- DCA dichloroacetec acid
- DCA also stimulates lactic acid oxidation in animal tissues and significantly decreases lactic acid levels and overall morbidity in patients with lactic acidosis [Stacpoole et al., N. Eng. J. Med 309:390 (1983); Blackshear et al., Diabetes Care 5:391 (1982)].
- DCA reduces circulating triglyceride and cholesterol concentrations in obese [Felts et al., Diabetes, 25 (suppl):363 (1976)] and diabetic [Hayek et al., Metabolism 29:120 (1980); Riles et al., Diabetes 28:852 (1979) animals.
- DCA also markedly decreases blood cholesterol levels in patients with various forms of hyperlipidemia [Stacpoole et al., N. Eng. J. Med. 298:526 (1978); Moore et al., Atherosclerosis 33:285 (1979)].
- DCA is toxic to lower animals and humans, particularly upon chromic administration. It has been reported that a human patient who received DCA for about four months developed a mild polyneuropathy that resolved when treatment stopped [Moore et al., ibid.]. Chronic administration of DCA to lower animals in doses exceeding those used clinically also induces a reversible peripheral neuropathy, changes in testicular morphology and lenticular opacities [Stacpoole, N. Eng. J. Med. 300:372 (1979)].
- DCA is known to oxidize in vivo to glyoxylate and subsequently to oxalate [Demangre et al., Biochem. Biophys. Res. Comm. 85:1180 (1978); Harris et al., Arch. Biochem. Biophys. 189:364 (1978)].
- Oxalate is known to cause neurotoxicy [Bilbao et al., Can. J. Neurol. Sci. 3:63 (1976)] and lenticular opacities [Fielder et al., Br. J. Ophthal. 64:782 (1980)], and may be at least partly responsible for the toxic effects associated with the chronic administration of DCA.
- the present invention provides a novel chemical compound prepared by reacting thiamine or a pharmaceutically active derivative thereof, e.g., a thiamine metabolite and dichloroacetic acid.
- the present invention also provides a method for preparing the above-described compound comprising reacting dichloroacetic acid or a reactive derivative thereof with thiamine and recovering the reaction product.
- the present invention also provides a pharmaceutical composition in unit dosage form adapted for administration to a lower animal or human for the treatment of a metabolic disease comprising a therapeutically effective amount of (1) the above-described compound or anion salt of a pharmaceutically acceptable cation and dichloroacetic acid and (2) an amount of thiamine or a pharmaceutically active derivative thereof sufficient to reduce the toxicity to the lower animal or human of the compound or salt of dichloroacetic acid.
- a method for the treatment of a metabolic disease comprising the administration to a lower animal or human in need thereof a therapeutically effective amount of the above-described compound or a salt of a pharmaceutically acceptable cation and dichloroacetic acid and an amount of thiamine necessary to reduce the toxicity to the lower animal or human of the compound or the salt.
- DCA Dichloroacetic acid
- Acid free dichloroacetic acid
- Thiamine or a pharmaceutically active derivative thereof may be administered according to the present invention (1) in the form of a compound produced by reaction thereof with dichloroacetic acid, (2) in the form of a mixture with the salt of dichloroacetic acid, or (3) prior to, subsequent to, or substantially simultaneously with the administration of DCA.
- the pharmaceutical composition of the invention preferably contains a pharmaceutically acceptable carrier suitable for rendering the compound or mixture administrable orally as a tablet, capsule or pill, or parenterally or transdermally.
- the active ingredient may be admixed or compounded with any conventional, pharmaceutically acceptable carrier.
- any mode of administration, vehicle or carrier heretofore employed for the administration of DCA alone may be utilized for preparing and administering the pharmaceutical compositions of the present invention.
- Illustrative of such methods, vehicles and carriers are those described by Stacpoole et al. [N. Eng. J. Med., 309:390 (1983) and N. Eng. J. Med. 298:526 (1978)], the disclosures of which are incorporated herein by reference.
- Those skilled in the art, having been exposed to the principles of the invention will experience no difficulty in determining suitable and appropriate vehicles, excipients and carriers or in compounding the active ingredients therewith to form the pharmaceutical compositions of the invention.
- Thiamine is capable of reacting with the acid to form either an ester, amide or salt-complex, depending upon the reaction conditions employed.
- the acid will also react with metabolites of thiamine, such as thiamine pyrophosphate, to form similar compounds.
- the present invention includes any pharmaceutically acceptable reaction product formed by reacting the acid or reactive derivative thereof with thiamine or any derivative thereof.
- the therapeutically effective amount of DCA or acid/thiamine compound to be included in the pharmaceutical composition of the invention depends, in each case, upon several factors, e.g., the type, size and condition of the animal, the metabolic disorder to be treated, the intended mode of administration, the capacity of the animal to incorporated the intended dosage form, etc.
- an amount of DCA or acid/thiamine compound is included in each dosage form to provide an amount of DCA or acid employed in conventional pharmaceutical compositions containing DCA alone (Cf. Stacpoole et al., supra), i.e., from about 100 to about 10,000 mg, preferably from about 100 to about 5,000 mg.
- the amount of thiamine to be included in the composition will depend upon the same factors noted above, and in particular, upon the degree of toxicity associated with the pressure of DCA or acid in the animal undergoing treatment. Generally, however, an amount of thiamine is included in the composition, either in admixture with DCA or as a compound with the acid or derivative thereof to provide a mass ratio of thiamine to DCA or acid of from about 1 ⁇ 10 -5 :1 to about 10:1, preferably from about 1 ⁇ 10 -3 :1 to about 0.2:1.
- the DCA employed in the pharmaceutical compositions and methods of treatment of the invention may comprise the salt of dichloroacetic acid and any pharmaceutically acceptable cation, e.g., alkali metals such as sodium, potassium, lithium, alkaline earth metals such as magnesium, calcium, heavy metals such as manganese, iron, zinc, etc., and ammonium, etc.
- alkali metals such as sodium, potassium, lithium
- alkaline earth metals such as magnesium, calcium
- heavy metals such as manganese, iron, zinc, etc.
- ammonium etc.
- an alkali metal salt, of the acid most preferably the sodium salt.
- the compound, compositions and method of the invention are useful for the treatment of a wide variety of metabolic disorders. Those skilled in the art will appreciate that the invention is applicable for the treatment of any disorder for which the administration of DCA has been found to be effective. Exemplary of such disorders are diabetes mellitus, hyperlipidemia (hypercholesterolemia, hypertriglycidemia, or both) and lactic acidosis.
- the dichloroactic acid-thiamine compound or the mixture of DCA and thiamine may be solubilized in a suitable solvent, e.g., water, conventional physiological buffer solutions (phosphate, bicarbonate, lactate) or other medicinal solvents such as dimethyl sulfoxide, etc., and lyophilized for later reconstitution with the above-noted carrier media for parenteral, oral or transdermal administration.
- a suitable solvent e.g., water, conventional physiological buffer solutions (phosphate, bicarbonate, lactate) or other medicinal solvents such as dimethyl sulfoxide, etc.
- composition of the invention may also be separately packaged in kit form, i.e., one package comprising the dichloroacetic acid-thiamine compound or DCA salt in unit dosage form, and the other package comprising thiamine or pharmaceutically active derivative thereof in unit dosage form.
- kit form i.e., one package comprising the dichloroacetic acid-thiamine compound or DCA salt in unit dosage form, and the other package comprising thiamine or pharmaceutically active derivative thereof in unit dosage form.
- the respective dosages could be separately administered to the patient or combined before administration as a single dose.
- compositions of the invention to be administered in accordance with the method of the invention to a patient will depend upon those factors noted above.
- DCA or acid/thiamine compound are administered to provide dosages of DCA or acid conventionally employed in the treatment of metabolic disorders, i.e., from about 1 to about 100 mg/kg, preferably from about 10 to about 50 mg/kg, the frequency of administration and duration of treatment being dependent upon the type and nature of the animal and metabolic disorder treated.
- the amount of thiamine or pharmaceutically active derivative thereof co-administered with the acid component, either in admixture or in the form of a reaction product therewith is that necessary to provide the mass ratios of thiamine to DCA or acid set forth hereinabove.
- dichloroacetate and thiamine are provided in the biological system in an active form capable of performing their therapeutic function, i.e., amelioration of the metabolic disorder and reduction of the toxic effects of the dichloroacetate.
- the invention is illustrated by the following non-limiting example.
- DCA increased SI over 3-fold above control and decreased RCT 25%. Addition of B 1 reduced by 41% the SI seen with DCA alone and normalized RCT. Plasma DCA ( ⁇ g/ml) was not significantly affected by B 1 . After 2 mos., urinary OX ( ⁇ g/ml) was 86% above control in DCA rats but only 28% above control DCA+B 1 rats.
Abstract
Description
TABLE 1 ______________________________________ Group SI RCT DCA OX ______________________________________ Control 12 ± 4 143 ± 7 -- 79 ± 6 DCA 39 ± 11 108 ± 6 291 ± 2 147 ± 12 DCA + B.sub.1 23 ± 6 148 ± 8 282 ± 12 101 ± 12 ______________________________________
Claims (30)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/584,994 US4558050A (en) | 1984-03-01 | 1984-03-01 | Treatment of metabolic disorders with dichloroacetate-thiamine preparations |
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US06/584,994 US4558050A (en) | 1984-03-01 | 1984-03-01 | Treatment of metabolic disorders with dichloroacetate-thiamine preparations |
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US4558050A true US4558050A (en) | 1985-12-10 |
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US06/584,994 Expired - Lifetime US4558050A (en) | 1984-03-01 | 1984-03-01 | Treatment of metabolic disorders with dichloroacetate-thiamine preparations |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4801597A (en) * | 1985-06-11 | 1989-01-31 | University Of Florida | Certain inositol-nicotinate ester derivatives and polyionic complexes therefore useful for treating diabetes meuitus, hyperlipidemia and lactic acidosis |
WO2005072738A1 (en) * | 2004-01-30 | 2005-08-11 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US20070191408A1 (en) * | 2004-01-30 | 2007-08-16 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
WO2008025870A1 (en) * | 2006-08-28 | 2008-03-06 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US20080206313A1 (en) * | 2004-01-30 | 2008-08-28 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US7705016B2 (en) | 2003-02-13 | 2010-04-27 | Albert Einstein College Of Medicine Of Yeshiva University | Regulation of food intake by modulation of long-chain fatty acyl-CoA levels in the hypothalamus |
-
1984
- 1984-03-01 US US06/584,994 patent/US4558050A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
Jacob Gutman, Modern Drug Encyclopedia and Therapeutic Guide, 1941. * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4801597A (en) * | 1985-06-11 | 1989-01-31 | University Of Florida | Certain inositol-nicotinate ester derivatives and polyionic complexes therefore useful for treating diabetes meuitus, hyperlipidemia and lactic acidosis |
US7705016B2 (en) | 2003-02-13 | 2010-04-27 | Albert Einstein College Of Medicine Of Yeshiva University | Regulation of food intake by modulation of long-chain fatty acyl-CoA levels in the hypothalamus |
WO2005072738A1 (en) * | 2004-01-30 | 2005-08-11 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US20070191408A1 (en) * | 2004-01-30 | 2007-08-16 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US20080206313A1 (en) * | 2004-01-30 | 2008-08-28 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
US8119651B2 (en) | 2004-01-30 | 2012-02-21 | Biotie Therapies Corp. | Compositions useful especially for treatment or prevention of metabolic syndrome |
WO2008025870A1 (en) * | 2006-08-28 | 2008-03-06 | Faron Pharmaceuticals Oy | Compositions useful especially for treatment or prevention of metabolic syndrome |
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Owner name: UNIVERSITY OF FLORIDA, 207 TIGERT HALL, GAINESVILL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:STACPOOLE, PETER W.;REEL/FRAME:004267/0752 Effective date: 19840605 Owner name: FLORIDA, UNIVERSITY OF,FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:STACPOOLE, PETER W.;REEL/FRAME:004267/0752 Effective date: 19840605 |
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